Fenofibrate Reduces the Severity of Neuroretinopathy in a Type 2 Model of Diabetes without Inducing Peroxisome Proliferator-Activated Receptor Alpha-Dependent Retinal Gene Expression.

Jennifer M Enright,Rithwick Rajagopal,Christina Thebeau,Clay F Semenkovich,Sheng Zhang,Xiaodong Zhang,Veda Gadiraju,Emily Siebert,Alexander Jin,Shiming Chen

doi:10.3390/jcm10010126

Abstract

Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a DR mouse model, db/db, we tested the hypothesis that fenofibrate slows early DR progression by activating PPARα in the retina. Relative to healthy littermates, six-month-old db/db mice exhibited elevated serum triglycerides and cholesterol, retinal gliosis, and electroretinography (ERG) changes including reduced b-wave amplitudes and delayed oscillatory potentials. These pathologic changes in the retina were improved by oral fenofibrate. However, fenofibrate did not induce PPARα target gene expression in whole retina or isolated Müller glia. The capacity of the retina to respond to PPARα was further tested by delivering the PPARα agonist GW590735 to the intraperitoneal or intravitreous space in mice carrying the peroxisome proliferator response element (PPRE)-luciferase reporter. We observed strong induction of the reporter in the liver, but no induction in the retina. In summary, fenofibrate treatment of db/db mice prevents the development of early DR but is not associated with induction of PPARα in the retina.

Highlights

IntroductionDiabetes is associated with a high burden of retinal disease, with diabetic retinopathy (DR) affecting over 4 million patients and diabetic macular edema over 1 million patients in the United States alone [1]
The leptin-receptor mutant db/db mouse develops a number of metabolic abnormalities, including obesity, altered lipid profile, and diabetes, all of which are exacerbated by a high-fat diet [22,33]
Our results confirm that oral fenofibrate alters metabolism in a mouse model of type 2 diabetes by altering circulating lipids, modulating gliosis and improving ERG

Summary

Introduction

Diabetes is associated with a high burden of retinal disease, with diabetic retinopathy (DR) affecting over 4 million patients and diabetic macular edema over 1 million patients in the United States alone [1]. Patients with vision-threatening disease may benefit from available treatment options, including vascular endothelial growth factor (VEGF) inhibitors, steroids, pan-retinal photocoagulation, and vitrectomy, but not all patients respond to these therapies [2,3,4]. There is a need for treatments that can slow progression of disease before it becomes vision threatening. Risk in Diabetes (ACCORD) studies to slow the progression of mild to moderate nonproliferative DR and reduce the need for treatment of macular edema [5,6]. In patients with extant diabetic macular edema, fenofibrate used in conjunction with VEGF inhibitors led to greater improvement than VEGF inhibitors alone [7]. Fenofibrate shows promise in the treatment of DR, its mechanism of action remains unclear

Methods

Results

Conclusion